The main goal of the Collaborative Study on the Genetics of Alcoholism (COGA) is to localize, identify and characterize genes influencing alcohol dependence and related phenotypes. A primary focus is to continue to identify genes in which variants affect the risk for alcoholism and related disorders. This includes identifying additional genes in adults, including testing the results from other studies and from joint analyses of multiple studies. Related to this is the characterization of the molecular and cellular mechanisms through which the variants act. Another major focus is the study of adolescents and young adults, to examine genetic effects across development and to understand the environmental factors that affect expression of genetic risk in this critical age range. This will be carried out through a prospective study in which participants are carefully assessed for many behavioral and neural phenotypes. An important part of this is the development of novel behavioral and neurophysiological phenotypes related to risk for alcoholism and to brain functions, which can help both in identifying relevant genes and understanding the mechanisms through which they work. We will test the hypothesis that genes affecting risk for alcoholism and related phenotypes in adults also affect related phenotypes in adolescents. We will also test the hypothesis that exposure to alcohol during key developmental stages causes epigenetic modifications that alter gene expression thereby affecting the long-term risk for alcoholism and its sequelae. Supporting these efforts will be the maintenance of high quality databases and biological materials, and making these available to approved external investigators. Together these aims go from identifying genes in which variants affect risk for alcoholism to understanding how they act at multiple levels, from molecular and cellular to behavioral, neurophysiological and phenotypic levels as a function of development. We anticipate that through the delineation of the pathways and genes contributing to alcohol dependence and alcohol use and abuse, we will directly impact the ability to successfully treat alcohol problems and intervene in those at greatest risk. PUBLIC HEALTH RELEVANCE: Alcoholism is a major social and health problem. It has been estimated that misuse of alcohol costs the US over $180 billion per year, and that alcohol is the third leading cause of loss of disability adjusted life years in Western countries. Understanding how genetic variations affect the risk for alcoholism will make important contributions to prevention and treatment of this serious disease.